مطالعه نظری ساختاری و الکترونی داروی S-فنوپروفن با استفاده از محاسبات تابعیت چگالی

نوع مقاله : مقاله پژوهشی

نویسندگان

1 گروه شیمی آلی، دانشکده شیمی دارویی دانشگاه علوم پزشکی ، تهران، ایران

2 دانشگاه علوم پزشکی آزاد اسلامی تهران دانشکده شیمی

3 گروه شیمی، واحد ورامین- پیشوا، دانشگاه آزاد اسلامی، ورامین، ایران

چکیده

در این پژوهش، سنجش و بررسی اثرات نامستقر شدن الکترونی، برهمکنش‌های دوقطبی- دوقطبی بر روی خواص ساختاری و الکترونی و میزان واکنش­پذیری ساختار دو انانتیومر داروی فنوپروفن انجام شده است. محاسبات مکانیک کوانتومی تئوری تابع چگالی الکترونی برای دستیابی به اطلاعات ساختاری و رفتار دینامیکی دو انانتیومر داروی فنوپروفن در فاز گازی و حلال، در سطح نظری B3LYP و سری پایه6-31G*  و نیز پارامترهای پوشانندگی (Nuclear magnetic resonance) NMR با استفاده از روش (Gauge-Independent Atomic Orbitals) GIAO انجام شد. همچنین تحلیل NBO (Natural Bond Orbital) برای محاسبه اثرات انتقال الکترونی ناشی از برهمکنش استریو الکترونی و ممان های دوقطبی، اندیس­های واکنش پذیری، انرژی اوربیتال های مولکولی و گپ انرژی، نمودار دانسیته سطحDOS  (Density Of Staters) و دانسیته بار اتمی مولیکن انجام شد. با توجه به نتایج حاصل از محاسبات انرژی هر دو انانتیومر داروی فنوپروفن، چپ گرد (S) و راست گرد (R) انرژی یکسانی دارند و با توجه به مطالعات تجربی انجام شده انانتیومر S پایدارتر است در نتیجه محاسبات بر روی انانتیومر S-فنوپروفن انجام شده است. نتایج حاصل از محاسبات نظری در سطح B3LYP/6-31G* نشان داد، گپ انرژی انانتیومر داروی S-فنوپروفن (الکترون ولت 5265/5Eg =) است. تعیین اندیس­های واکنش پذیری داروی S-فنوپروفن، نشان دهنده میزان الکترونخواهی و سختی بالا (پایداری) و واکنش پذیری کم این ترکیب است.

کلیدواژه‌ها


عنوان مقاله [English]

Theoretical Study of structural and electronic of S-Fenoprofen drug by Density Functional Calculation

نویسندگان [English]

  • masoumeh shahi 1
  • Elaheh Sadeghi Madiseh 2
  • Fatemeh Azarakhshi 3
  • Sepideh Shokri Shams 2
1 Department of Organic Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
2 Department of Organic Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
3 Department of Chemistry, Varamin-Pishva Branch, Islamic Azad University, Varamin, Iran
چکیده [English]

In this study is to measure and evaluate the effects of electron instability, dipole-dipole interactions on the structural and electronic properties, and the structural reactivity of the Fenoprofen drug. Quantum mechanical calculations of electron density function theory were performed to obtain the structural information and the dynamic behavior of two Fenoprofen enantiomers in the gas and solvent phases, at the B3LYP/6-31G* level of theory, and Nuclear Magnetic Resonance (NMR) shielding tensors were calculated by using the Gauge Independent Atomic Orbital (GIAO) method. Also, NBO (Natural Bond Orbital) analysis was performed to calculate the effects of electron transfer due to the interaction of electron stereo and dipole moments, reactivity indices, the energy of molecular orbitals, and bond gaps energy, the density of state (DOS), and molecular atomic charge density.
According to the results of the energy calculations of both enantiomers, it was found that both Fenoprofen’s enantiomers, left-handed (S) and right-handed (R) have the same energy, and also according to the experimental studies, the S-enantiomer is more stable, so the rest of the calculations have been performed on the S-Fenoprofen enantiomer. The results of theoretical calculations at the level of B3LYP/6-31G* showed that the energy gap of the enantiomer is S-Fenoprofen (Eg =5.5265 eV). Determination of reactivity indices of S-Fenoprofen indicates high electron demand and hardness (stability) and low reactivity of this compound.

کلیدواژه‌ها [English]

  • Fenoprofen
  • Density Function Theory
  • Thermodynamic Functions
  • Enantiomer
  • Natural bond orbital
[1] A. J .Hutt, J. Caldwell, “The importance of stereochemistry in the clinical pharmacokinetics of the 2-arylpropionic acid non-steroidal anti-inflammatory drugs,” Clinical Pharmacokinetics, 9, 371-373, 1984.
[2] B. A. Hendriksen, J. D. Williams, “Characterization of calcium fenoprofen 2. Dissolution from formulated tablets and compressed rotating discs,” International journal of pharmaceutics, 69, 175-180, 1991.
[3] C. Patrono, G. Ciabattoni, D. Grossi-Belloni, “In vitro and in vivo inhibition of prostaglandin synthesis by fenoprofen, a non-steroid anti-inflammatory drug,” Pharmacological research communications, 6, 509-518,  1974.
[4] S. Abramson, H. Korchak, R. Ludewig, H. Edelson, K. Haines, R. I. Levin, R. Herman, L. Rider, S. Kimmel, G. Weissmann, “Modes of action of aspirin-like drugs,” Proceedings of the national academy of sciences, 82, 7227-7231, 1985.
[5] F. J. de Abajo, M. J. Gil, V. Bryant, J. Timoner, B. Oliva, L. A. García-Rodríguez, “Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case–control study in a new general practice database, ” European journal of clinical pharmacology, 69, 691-701, 2013.
[6] H. Okanobu, M. Ito, S. Tanaka, S. Onogawa, M. Akagi, H. Oh-e, S. Nagata, S. Okamoto, T. Kuwai, S. Cho, Y. Matsumoto, “Evaluation of individual risk in nonvariceal gastrointestinal bleeding patients with NSAID administration: a multicenter study in Japan,” Digestion, 86, 187-193,  2012.
[7] S. S. Adams, P. Bresloff, C. G. Mason, “Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (-)-isomer,” Journal of pharmacy and pharmacology, 28, 256-257, 1976.
[8] A. J. Hutt, J. Caldwell, “The metabolic chiral inversion of 2-arylpropionic acids- a novel route with pharmacological consequences,” Journal of pharmacy and pharmacology, 35, 693-704, 1983.
[9]Z. N. Gaut, H. Baruth, L. O. Randall, C. Ashley, J. R. Paulsrud, “Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthesis,” Prostaglandins, 10, 59-66, 1975.
[10] A. P. Roszkowski, W. H. Rooks, A. J. TOMOLONIS, L. M. MILLER, “Anti-inflammatory and analgetic properties of d-2-(6'-methoxy-2'-naphthyl)-propionic acid (naproxen),” Journal of Pharmacology and Experimental Therapeutics, 179, 114-123, 1971.
[11] A. Rubin,  M. P. Knadler, P. P. Ho, L. D. Bechtol, R. L. Wolen, “Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans,” Journal of pharmaceutical sciences, 74, 82-84, 1985.
[12] A. M. Evans, “Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs,” European journal of clinical pharmacology, 42, 237-256, 1992.
[13] C. Volland, H. Sun, L. Z. Benet, “Stereoselective analysis of fenoprofen and its metabolites,” Journal of Chromatography B, Biomedical sciences and applications, 534, 127-138, 1990.
[14] S. D. Hall, M. Hassanzadeh‐Khayyat, M. P. Knadler, P. R. Mayer, “Pulmonary inversion of 2‐arylpropionic acids: influence of protein binding,” Chirality, 4, 349-352, 1992.
[15] B. W. Berry, F. Jamali, “Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat,” Journal of Pharmacology and experimental therapeutics, 258, 695-701, 1991.
[16] G. Geisslinger, O. Schuster, K. P. Stock, D. Loew, G. L. Bach, K. Brune, “Pharmacokinetics of S (+)-and R (−)-ibuprofen in volunteers and first clinical experience of S (+)-ibuprofen in rheumatoid arthritis,” European journal of clinical pharmacology, 38, 493-497, 1990.
[17] S. Sundaram, R. Jayaprakasam, M. Dhandapani, T. S. Senthil, V. N. Vijayakumar, “Theoretical (DFT) and experimental studies on multiple hydrogen bonded liquid crystals comprising between aliphatic and aromatic acids,” Journal of molecular liquid, 243, 14-21, 2017.
[18] A. H. Mashhadzadeh, A. M. Vahedi, M. Ardjmand, M. G.  Ahangari, “Investigation of heavy metal atoms adsorption onto graphene and graphdiyne surface: a density functional theory study,” Superlattices and microstructures, 100, 1094-1102, 2016.
[19] S. Hadidi, F. Shiri, M. Norouzibazaz, “Mechanistic study of fenoprofen photoisomerization to pure (S)-fenoprofen: a DFT study,” Structural chemistry, 31, 115-122, 2020.
[20] K. Dermeche, N. Tchouar, D. Harkati, S. Belaidi, K. Bentayeb, A. Rouane, “Molecular modeling of reactivity and vibrational spectrum raman of thalidomide enantiomers R and S using density functional theory and hartree-fock methods,” Quantum matter, 6, 1-7, 2017.
[21] E. Soleymani, H. Alinezhad, M. Darvish. G, M. Tajbakhsh, “Enantioseparation performance of CNTs as chiral selectors for the separation of ibuprofen isomers: a dispersion corrected DFT study,” Journal of materials chemistry B, 5, 6920-6929, 2017.
[22] A. Szabo, N. S. Ostlund, “Modern quantum chemistry: introduction to advanced electronic structure theory,” Courier corporation, 2012.
[23] P. W. Atkins, R. S. Friedman, “Molecular quantum mechanics,”  5th edition. Oxford university press, 2011.
[24] D. W. Rogers, “Computational Chemistry using the PC,” John wiley & sons, 2003.
[25] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, “Gaussian 09,” Gaussian. inc, wallingford, CT, 32, 5648-5652, 2009.
[26] E. D. Glendening, C. R. Landis, F. Weinhold, “NBO 6.0: Natural bond orbital analysis program,” Journal of computational chemistry, 34, 1429-1437, 2013.
[27] P. Politzer, J. M. Seminario, editors, “Modern density functional theory: a tool for chemistry,” Elsevier, 2, 405, 1995.
[28] H. O. Ammar, T. S. Makram, S. Mosallam, “Effect of polymers on the physicochemical properties and biological performance of fenoprofen calcium dihydrate-triacetyl-β-cyclodextrin complex,” Pharmaceutics, 9, 23, 2017.
[29] S. Murthy-patnala, M. Khagga, R. bhavani, “Monotropically more stable fenoprofen calcium dihydrate,” Journal of applicable chemistry, 4, 895-902, 2015.
[30] S. H. Sarijo, M. L. Jadam, F. M. Saleh, “Intercalation of fenoprofen into layered double hydroxide for the formation of controlled release anti-inflammatory drug,” Advanced materials research, 1142, 230-233, 2017.
[31] A. D. Becke, “Density functional thermochemistry. I. The effect of the exchange only gradient correction,” The journal of chemical physics, 96, 2155-2160, 1992.
[32] J. E. Carpenter, F. Weinhold, “Analysis of the geometry of the hydroxymethyl radical by the “different hybrids for different spins” natural bond orbital procedure,” Journal of molecular structure, Theochem, 169, 41-62, 1988.
[33] A. Lesarri, A. Vega-Toribio, R. D. Suenram, D. J. Brugh, D. Nori-Shargh, J. E. Boggs, J. U. Grabow, “Structural evidence of anomeric effects in the anesthetic isoflurane,”  Physical chemistry chemical physics, 13, 6610-6618, 2011.
[34] N. Masnabadi, D. Nori-Shargh, F. Azarakhshi, H. Zamani Ganji, M. Abbasi, S. Karamad, G. A. Kasaei, “Hybrid-DFT, MO study and NBO interpretation of conformational behaviors of 2-halo-1, 3-dioxanes and their dithiane and diselenane analogs,” Phosphorus sulfur silicon relat elem, 187, 305-320, 2012.
[35] S. Muthu, N. R. Sheela, S. Sampathkrishnan, “Density functional theory and ab initio studies of vibrational spectra of 2-bis (2-chloroethyl) aminoperhydro-1,3,2-oxazaphosphorinane-2-oxide,” Molecular simulation, 37, 1276-1288, 2011.
[36] S. Hadidi, F. Shiri, M. Norouzibazaz and Farshad Shiri, “A theoretical investigation of the flurbiprofen methyl ester isomerization as the main step in the photopreparation of anti-inflammatory medicine (S)-flurbiprofen: A DFT study”, Current Chemistry Letters, 9, 161–170, 2020.
 
[37] M. Kwiatkowska, A. Wzorek, A. Kolbus, M. Urbaniak, J. Han, V.A. Soloshonok, K.D. Klika, “Flurbiprofen: A Study of the Behavior of the Scalemate by Chromatography, Sublimation, and NMR”, Symmetry, 13, 543, 2021.